The overall goal of the proposed studies is to determine the cellular and molecular mechanisms surrounding the interaction between the NOS and ET pathways in the inner medulla of the kidney in response to high salt. We predict that the intrarenal production of ET in response to high salt intake activates the abundant ETB receptors in the inner medulla. Our hypothesis predicts that activation of the ETB receptors in the renal inner medulla will result in a stimulation of NOS and subsequent production of NO which in turn inhibits Na reabsorption. These mechanisms contribute to the kidney's ability to control sodium excretion, and therefore, play an important role in fluid-volume regulation and the control of blood pressure. Specific Aim 1. To test the hypothesis that ETB receptor stimulation inhibits Na transport via NO production in renal inner medullary collecting duct cells. Specific Aim 2. To test the hypothesis that ETB receptor stimulation increases Na excretion via NOS 1-mediated NO production in the renal inner medulla. Specific Aim 3. To test the hypothesis that the mechanism of NOS 1-mediated NO production in the renal inner medulla is through NOS 1 dephosphorylation.